ClinVar Genomic variation as it relates to human health

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29056246, 27959697, 28007337, 30283815, 31487502, 31468518, 29100083, 34489640, 33258288, 33425808, 34102571)

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This variant has previously been described as disease causing for Ataxia, ClinVar lists this variant as pathogenic (Variation ID: 195935) and uncertain (Variation ID: 195935) and likely pathogenic (ID: 195935). This variant is absent parents. PolyPhen: Probably damaging ; Align-GVGD: C0; MutationTaster: Disease causing Conservation_nt: high; Conservation_aa: weak; This variant is absent in population databases.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000195935, PS1_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 28007337, 29100083, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280773,VCV001285568, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.889, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4, PM5_STR, PS3_MOD, PM2_SUP, PP2, PP3

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1393 of the CACNA1A protein (p.Val1393Met). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 31468518). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function. ClinVar contains an entry for this variant (Variation ID: 195935). This variant is also known as NM_023035.2:c.4186G>A (p.V1396M). This missense change has been observed in individual(s) with epileptic encephalopathy and ataxia, tremor, developmental delay, and epilepsy (PMID: 28007337, 29056246, 29100083, 30283815). In at least one individual the variant was observed to be de novo.

The alteration results in an amino acid change:_x000D_ _x000D_ The c.4177G>A (p.V1393M) alteration is located in coding exon 26 of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 4177, causing the valine (V) at amino acid position 1393 to be replaced by a methionine (M). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CACNA1A c.4177G>A alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.4177G>A (p.V1393M) alteration has been observed de novo in multiple unrelated affected patients. Common clinical features include seizures, ataxia, tremors, developmental delay, and intellectual disability (Travaglini, 2017; Butler, 2017; Cordeiro, 2018; Costain, 2019; Jiang, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.V1393 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.V1393 amino acid is located in the S5 transmembrane segment of domain III of the Cav2.1 P/Q type voltage-dependent calcium channel. The S5 and S6 helices line the inner pore surface of the ion channel (Rajakulendran, 2012). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis using whole cell voltage-clamp recordings of the mouse homologous variant in HEK293 cells demonstrated that the p.V1393M alteration increased peak density compared to wild type and altered current kinetics with a steeper activation curve and midpoint of activation that was more hyperpolarized. In addition, expression levels of mutant protein in the cell membrane was 50% of wild type expression levels (Jiang, 2019). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.V1393M alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Our laboratory reported dual molecular diagnoses in CACNA1A (NM_001174080.1, c.4177G>A) and SLC26A1 (NM_022042.2, c.1487T>G) in one individual with reported features of intractable epilepsy, global developmental delay, tremor, ataxia, hyperlipidemia, growth hormone deficiency, and stable right optic nerve glioma. Missense and truncating variants in CACNA1A have been reported in patients with epilepsy (PMID:18940563;PMID:21703448)

Variant interpreted as Pathogenic and reported on 12-31-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.